PHYSICIANS MAY one day treat patients who have shattered limbs, crippled joints and injured spines in a way that man never before dared to dream of: regrowing the damaged part - whole, perfect and uniseased.
For centuries, man has watched in wonder as the salamander regenerated its severed limbs, never imagining that complicated human parts could grow back in such a way. The halt and the lame could be made whole, it seemed, only by the healing waters of Bethesda or the touch of a god incarnate. But in recent years, scientists have grown back a frog's leg from elbow to toes and a rat's leg from shoulder to the top half of the elbow, with cartilage and bone, muscle, nerves and veins, all in awesome anatomical precision. One of the pioneers in the field, Dr. Robert Becker, chief of orthopedic surgery at the Veterans Administration Hospital in Syracuse, N.Y., has already applied the newly found healing mechanism to broken human bones, successfully knitting fractures that previously had failed to heal even after extensive surgical procedures. He and his colleagues have now reached the point where they can confidently predict that regeneration of human parts can and will be achieved, possibly in the next few decades.
A brave new world? Not a bit. The magic of regeneration has been with us all along, hidden in the wondrous complexity of every organism's bodyworks. These scientists are not performing miracles; they are witnessing them.
Their challenge, then, has been not so much to recreate a limb as to discover how some animals do so naturally. The chronicle of their quest reads like a detective story; for clue by clude, Becker and his colleagues have been unraveling a medical mystery that began with creation.
The tale begins with a few know biological principles about regeneration that were to serve as the departure point for their search. The way regenerative healing works has been observed, if not explained, for hundreds of years; the process still seems so magical that even the most clinical of researchers must shake his head in amazement as he watches the microscopic metamorphosis unfold.
The body of every animal, from the flatworm on up the evolutionary scale, possesses primitive, undifferentiated cells that could best be described as being like raw clay. When a creature which can regenerate loses a lim, these cells migrate to the injury, forming a mass called a blastema. Some of the mature, specialized cells at the site of the injury dedifferentiate, reverting to primitive form, and add further to the blastema. The blastema then respecializes, transforming itself into whatever types of cells are needed to replace the missing part - bone cells, cartilage cells and so forth. Somehow, the blastema absorbs information about what to produce along the way, so that at the appropriate moment, it creates an elbow joint or a tibia or a fibula, a left leg or a right one. Two Importan Clues
THE FIRST formal paper on regeneration was written by the great Italian physiologist Luigi Spallanzani and appeared in 1768. Spallanzani's experiments uncovered the first two important clues: The younger the animal, the greater its capacity for regeneration; and the lower an animal is on the evolutionary scale, the greater its capacity for regeneration.
This latter finding was especially interesting, for it provided a clue in itself. The lower orders that regenerate are biologically just as complicated as man; their parts are just as difficult to replace. The main difference is - and this was later to become a significant clue - that animals in the lower orders have comparatively more nerves in their extremities.
A third clue was buried in the writings of the late 1700s. Every time a creature is injured, an electrical charge is generated at the site of the injury. This phenomenon is called the current of injury, and it is proportionate to the severity of the wound.
It was not until some 180 years later that scientists again began to delve into the mystery of regeneration. In 1945, the biologist Meryl Rose (a retired professor of anatomy at Tulane University College of Medicine who is currently affiliated with Woods Hole Marine Biological Laboratories) amputated the forelegs of some frogs below the elbows. Thinking he could perhaps promote growth by preventing the injuries from scarring over, he bathed the stumps of the frogs' limbs in a strong salt solution.
The result was startling. About half of each amputated limb regenerated, developing new bone and muscle and in some case even showing the beginnings of digital growth. Thus Rose became the first to prove that an animal which cannot regenerate naturally can be made to do so artificially.
The next year, a Russian named Vladimirovic Polezhaev amputated frogs' legs in a similar fashion and then irritated the stumps by repeatedly jabbing them with needles. The result? Astonishingly, he regenerated about the same amount of growth that Rose had with the salt solution. It was possible that the salt not only had prevented scarring but, like the needle punctures, had actually exacerbated the injuries and thereby stimulated growth. Now there was another clue: Regeneration may somhow be connected to the severity of injury.
In the early 1950s, Marcus Singer, now a professor of anatomy at Case Western Reserve University in Cleveland, became the next to uncover important evidence. He tranferred nerves from a frog's healthy hind legs to the stump of its foreleg; his frog also regenerated about the same amount of growth that Rose's had. Singer's contribution to the collection of clues is an almost mathematical formulation: The nerve tissue required for regeneration must constitute at least 30 percent of the total tissue at the site of the injury.
Then, in 1958, a Russian named A.V. Zhirmunskii discovered that the current of injury is proportionate not just to the severity of the injury but also to the amount of nerve tissue in the area.
Becker's turn at medical detection also came in 1958. He assembled his evidence as a good detective would assemble his suspect: Injury is related to regeneration; nerve tissue is related to regeneration, and both injury and nerve tissue are related to the current of injury. Could the current of injury, Becker reasoned, thus be related to regeneration?
He measured the current of injury in a salamander's regenerating leg and in a frog's scarring stump. Sure enough, his findings seemed to support his hunch. On the day the legs were amputated, both creatures generated the same current of injury - a positive voltage. But there the similarity ended: As the frog's stump scarred over, the current of injury in its leg declined to zero; but the current of injury in the salamander's leg switched from a positive to a negative polarity and only then began to decline, reaching zero when regeneration was complete.
Becker had definitely discovered a connection between the current of injury and regeneration. In a sense, however, his discovery complicated rather than clarified the mystery. The way the current of injury worked in those limbs was simply not concurent with the way nerves are supposed to produce electricity.
Nerve fibers have traditionally been thought to respond to stimulation in only one way: Sodium penetrates into the nerve cell and potassium leaks out, creating a chemical reaction that generates a charge called an action potential. Whatever the stimulus - a gentle touch or an injury - the action potential is exactly the same. Moreover, each nerve fiber can create only one of these potentials at a time. Becker compares the system to that of a digital computer, which transmits single impulses in rapid succession.
Herein lay Becker's problem: How could the action potential - a constant - account for the switch from positive to negative polarity that he had seen in the salamander's current of injury? How could the action potential account for the fact that the current of injury lasted many days after the stimulated nerve cells should have either died or repaired themselves and ceased their impulses? How could the action potential, which responds in the same way to every stimulus, account for the fact that creatures feel intensities of pain?
Becker guessed that in additin to its digital-computer impulses, the central nervous system can carry steady currents and potentials - in the way an analog computer can. he further theorized that the body's analog computer system has an input signal - could it be pain? - that triggers an output signal which switches on the healing function.
To verify his theory, Becker measured the electrical potentials of different points on the skin of humans and other animals. He found an electrical field that roughly parallels the nervous system. A disturbance in that field, such as an injury, might stimulate cells to begin repairs.
Becker's theory ran counter even to basic textbook explanations of the nervous system, and medical men let him know it. "That cells are capable of sensing and responding to levels of electrical current is hardly universally accepted," he wrote in one medical journal. But he stuck to his convictions; and today, more than a decade later, doctors are coming to accept his hypothesis. "They no longer marchout of my lectures," he says. "The response has changed from complete rejection throught amused disbelief to - at present - almost enthusiastic acceptance." Bone Regeneration
AND NO WONDER. The experiments that Becker based on his unorthodox vision of the nervous system produced remarkable results. First, in 1964, Becker began to examine the spontaneous regeneration of human bone. Given the fact that bone is not well innervated, the theories about electrical stimulation would not apply - unless none could generate its own electricity. Becker knew that bone accommodates automatically to mechanical stress. When he measured the currents around a stressed bone, he discovered that it generated a positive charge on the stretched side (which dissolved some bone) and a negative charge on the other side (which built up bone and provided the necessary added support). Then Becker administered a negative charge to a mouse's broken leg bone to see if he could artificially stimulate bone grwoth. He did.
In 1964, Steven Smith, then a student of Meryl Rose and now an associate professor in the department of anatomy at the University of Kentucky, studied Becker's findings and got the idea of implanting a simple electrode right into the muscle tissue of the stump of a frog's leg. He soldered together a piece of platinum wire, which has a positive charge, and a piece of silver wire, which has a negative charge, and embedded the metal into the animal tissue - with the negative end at the stump - thus improvising a crude battery. It worked. He regenerated about as much growth as the Rose, Polezhaev and Singer experiments had the decade before.
Breakthrough followed breakthrough. Becker examined his healing frog bones under a microscope and saw that the blastema around the regenerating bone was coming from a blood clot that had formed there. (A frog's red blood cells are prime candidates for blastema, for, unlike the red blood cells of mammals, they have nuclei and thus can easily divide and dedifferentiate.)
His next step? He had a student expose frog blood to various levels of electrical current in order to find out exactly how much of a charge is needed to turn blood cells into blastema. Days passed, then months. The student administered smaller and smaller currents to the blood (high ones either did nothing or began to cook the cells), but he saw no evidence of change. Finally, the week before the student was supposed to quit and return to his classes, he found that blood cells revert to blastema at a few billionths of an ampere.
In 1973, armed with the knowledge of how much current produces a blastema, Becker decided to have the step from regenrating amphibians to regenerating mammals. He amputated a rat's foreleg below the shoulder and implanted the platinum-silver electrode device at the stump. Again, success - this time, the most exciting ever. The animal regenerated nerves and tissue and even formed the humerus, the upper-arm bone, complete with the rounded end that fits into the elbow joint. Other parts of the elbow joint began to take shape, including cartilage and two bony structures that Becker surmissed were the forerunners of the radius and ulna bones of the lower leg. Everything about the new growth was precisely as it had been in the original limb. And all this growth took place in just three days.
But then the growth ended; for the electrode remained implanted in the shoulder tissue, while the end of the stump, where regeneration was taking place, had grown beyond the reach of its vital current.
The rat's growth, though incomplete, was nevertheless significant, particularly in one respect: The fact that the rat, whose red blood cells have no nuclei, could form a blastema - probably from bone marrow - indicated that in all probability humans could do sso as well.
About this time in London, two newborn infants lost their fingers, and the fingers regenerated naturally. The explanation, in Becker'sview, probably lies with Spallanzani's early finding that the younger the creature, the better its ability to regenerate. But what was most significant about the babies' growth was that it indicated that the human body contains within its capacity for regeneration.
Later in 1973, Smith devised an electrode that would travel with the regenerating stump. Again he amputated a frog's leg below the elbow: With the new device, the frog's entire leg grew back.
The year 1973 marked a third triumph as well: Becker began using his findings about the body's electricity in experiments on human bone. A patient of his who had fractured his ankle two years earlier suffered from a mild diabetic condition that was interfering with the bone's ability to regenerate. The ankle had failed to mend despite two corrective operations; and the bone on both sides of the break had deteriorated.
Under normal circumstances, Becker would have had to amputate the leg. Instead, he implanted an electrode into the fracture and administered the same current that he found had divided the frog's red blood cells. He waited three months, the time an ankle fracture would normally take to heal, and the fracture regenerated. A sample of the new bone showed it to be normal in every respect. Clue in the Nerves
THE NEXT YEAR, during the course of routine experiments, Becker stumbled on another clue that finally shed considerable light on his nervous system theory. With the intention of impeding growth, he and his staff broke the tibia in a rat's leg and then cut the nerve that led to the broken lim, assuming that without a nerve supply the rat's bone would heal poorly, if at all. But the fracture healed well; the only drawback was that it took twice the normal time. Perhaps the severed end of the nerve needed time to degenerate, they thought. So they cut the nerve six days before breaking the bone. To their astonishment, the bone healed in the normal amount of time, as if the nerve had never been cut at all.
What was going on? They opened up the leg, only to discover that the nerve fiber had not healed. What had healed was the nerve's sheath of Schwann cells - one of a dozen types of cells that make up the "perineural group" - traditionally thought to serve no purpose other than the insulation of the nerve fiber. The perineural cells in the brain were known to carry a steady current - for what reason, no one knew. It now seemed apparent that Schwann cells also carry a steady current. This was proof enough for Becker that the analog computer system he had theorized was indeed contained in the perineural cells - cells that sheathe the entire central nervous system.
The perineural discovery is by no means the end of the tale. Experiments must still be conducted to determine if electrical regeneration is entirely safe. Could applications of electricity to the peripheral nervous system, for example, induce some sort of behavorial disorder? Or damage our cognitive powers? Every human body contains dormant cancer cells. Could an implanted electrode shock them into fatal multiplication?
Nevertheless, much of the mystery has been solved. only the last chapter - the most exciting one - has yet to be written. It may well describe the modern world as a Shangri-La where damaged human parts are simply cut off and grown back properly. Our future may lie not with the bionic man but with the natural man.
The replacement of arthritic hip joints with Teflon parts, for example, is now a costly and not altogether satisfactory operation. The Teflon wears out. If the device is implanted in a young person, it may have to be replaced some four or five times in the course of his life. And with each hip operation, there is the risk of infection, which can be a deadly prospect. The alternative - growing a natural hip - would be safer and cheaper.
We may also someday regenerate a damage heart. Becker has discovered that salamanders replace some 50 percent of their cardiac muscles by regeneration. And Polezhaev has cut away the scar tissue on the hearts of dogs which had suffered severe heart attacks; all of the hearts regenerated and less than 5 percent of the dogs died. We may even replace parts defective at birth, given that damaged genes do not garble the instructions given to the blastema.
Becker himself is hesitant to herald regeneration as an immediate cure for amputees. The replacement of severed parts, he says, is still pretty far off. Why not aim for more immediate uses that would be beneficial to greater numbers of people? Severing the spinal cord in man produces paraplegia because man's spinal cord does not regenerate. Becker, however, thinks that since salamanders regenerate their spinal cords, man's spinal cord could perhaps be electrically stimulated to do the same thing. It would take only a year to see whether electrical stimulation works without complications in a paraplegic dog or monkey. And if such stimulation works safely in them, it could be safely applied to humans. Uanswered Questions
THE OUTSTANDING disappointment of the entire regeneration tale is that no one is conducting that experiment with paraplegic animals. Why? Money. Becker's own $100,000 grant from the Veterans Administration just covers staff salaries. Experiments are costly; keeping paraplegic animals in particular is frightfully expensive.
Still, it must not be forgotten that the financial problem - serious though it is - is the only laggard in regeneration's exhilarating face toward the future. It is the promise of regeneration - not the problems - on which we must focus attention. Hundreds of questions wait to be answered.
Animals that regenerate don't get cancer. If a tumor is implanted in a lizard's body, which does not regenerate, it grows to fatal proportions. But if it is implanted in the tail, which does regenerate, the tumor disappears. If we learn how to turn on regeneration (controlled growth), can we learn to turn off cancer (uncontrolled growth)?
Hormones play an important role in regeneration. A chopped-up adrenal gland when implanted in a frog will generate some growth. Moreover, if the adrenal gland is removed from a lizard, the creature will lose its ability to regenerate its tail. If the hormone prolactin is then injected, the lizard will regain its regenerative potential. It has also been hypothesized that hormones secreted during stress can cause cancer. Prolactin is secreted during stress. Is there a connection? Do carcinogens impose a stress on the body, which then triggers a hormonal release that oversensitizes the body to its own electrical forces, thus sparking wild division of cells?
If a negative charge builds up bone and a positive charge dissolves bone, could positive charges have an effect on malignancies?
If pain is the input signal needed by the brain to trigger healing, does anethesia - the muffling of the pain signal - impede healing?
When power lines are stretched across the sea, amplifiers are put in at regular points to boost the current along. The body's electrical system may run the same way, equipped with special spots along the analog nervous system that boost the signals as they are carried to or from the brain. Becker has found that half of the traditional acupuncture points correspond to the spots in the nervous system that seem to be amplifiers of electricity. Could acupuncture simply involve the insertion of a metal needle into one of the amplifiers, short-circuiting the pain signal so that it never reaches the brain?
Does the body's sensitivity to electricity explain why reversals in the earth's magnetic field are related to the extinction of certain animals?
When one electrical field is imposed on another, the currents are altered. When one human being approaches another, do their biological electric systems overlap? Is this a scientific explanation for the "psychic" mystery of ESP?
The characteristics of the analog nervous system are such that it should be influenced by external electrical fields. Becker has already found experimental evidence that would indicate that electrical fields such as those produced by power transmission lines produce stress in animals - with consequent physical effects that are shocking indeed to the layman. What is the relation between this unseen electrical pollution and human stress?
The possibilities seem infinite. Each is like a silver key. Which one will open the door to a new world?